Bis Aromatic Compounds for Use as LTC4 Synthase Inhibitors

Abstract

There is provided compounds of formula I, wherein Y, ring A, D 1 , D 2a , D 2b , D 3 , L 1 , Y 1 , L 2 and Y 2 have meanings given in the description, and pharmaceutically-acceptable salts thereof, which compounds are useful in the treatment of diseases in which inhibition of leukotriene C 4 synthase is desired and/or required, and particularly in the treatment of a respiratory disorder and/or inflammation.

1 . A compound of formula I, 
       
         
           
           
               
               
           
         
         wherein 
         Y represents —C(O)— or —C(═N—OR 28 )—; 
         R 28  represents hydrogen or C 1-6  alkyl optionally substituted by one or more fluoro atoms; 
         either one of D 2a  and D 2b  represents D 2 , and the other represents —C(T)═; 
         D 1 , D 2  and D 3  respectively represent —C(R 1a )═, — c (R 1b )═ and —C(R 1c )═, or, each of these may alternatively and independently represent —N═; 
         ring A represents: 
       
       
         
           
           
               
               
           
         
         each of E a1 , E a2 , E a3 , E a4  and E a5  respectively represent —C(H)═, —C(R 2b )═, —C(R 2c )═, —C(R 2d )═ and —C(H)═, or, each of E at  E a2 , E a3 , E a4  and E a5  may alternatively and independently represent —N═; 
         one of R 2b , R 2c  and R 2d  represents the requisite -L 2 -Y 2  group, and the others independently represent hydrogen, -L 1a -Y 1a  or a substituent selected from X 1 ; 
       
       
         
           
           
               
               
           
         
         E b1  and E b2  respectively represent —C(R 3a )═ and —C(R 3b )═; 
         Y b  represents —C(R 3c )═ or —N═; 
         W b  represents —N(R 3d )—, —O— or —S—; 
         one of R 3a , R 3b  and, if present, R 3c  and R 3d , represents the requisite -L 2 -Y 2  group, and the remaining R 3a , R 3b  and (if present) R 3c  substituents represents hydrogen, -L 1a -Y 1a  or a substituent selected from X 2 , and the remaining R 3d  substituent (if present) represents hydrogen or a substituent selected from R z1 ; or 
       
       
         
           
           
               
               
           
         
         E c1  and E c2  respectively represent —C(R 4a )═ and —C(R 4b )═; 
         Y c  represents —C(R 4c )═ or —N═; 
         W c  represents —N(R 4d )—, —O— or —S—; 
         one of R 4a , R 4b  and, if present, R 4c  and R 4d  represents the requisite -L 2 -Y 2  group, and the remaining R 4a , R 4b  and (if present) R 4c  substituents represent hydrogen, -L 1a -Y 1a  or a substituent selected from X 3 , and the remaining R 4d  substituent (if present) represents hydrogen or a substituent selected from R z2 ; 
         R z1  and R z2  independently represent a group selected from Z 1a ; 
         R 1a , R 1b , R 1c , independently represent hydrogen, a group selected from Z 2a , halo, —CN, —N(R 6b )R 7b , —N(R 5d )C(O)R 6c , —N(R 5e )C(O)N(R 6d )R 7d , —N(R 5f )C(O)OR 6e , —N 3 , —NO 2 , —N(R 5g )S(O) 2 N(R 6f )R 7f , —OR 5h , —OC(O)N(R 6g )R 7g , —OS(O) 2 R 5i , —N(R 5k )S(O) 2 R 5m , —OC(O)R 5n , —OC(O)OR 5p  or —OS(O) 2 N(R 6i )R 7i ; 
         X 1 , X 2  and X 3  independently represent a group selected from Z 2a , or, halo, —CN, —N(R 6b )R 7b , —N(R 5d )C(O)R 6c , —N(R 5e )C(O)N(R 6d )R 7d , —N(R 5f )C(O)OR 6e , —N 3 , —NO 2 , —N(R 5g )S(O) 2 N(R 6f )R 7f , —OR 5h , —OC(O)N(R 6g )R 7g , —OS(O) 2 R 5i , —N(R 5k )S(O) 2 R 5m , —OC(O)R 5n , —OC(O)OR 5p  or —OS(O) 2 N(R 6i )R 7i ; 
         Z 1a  and Z 2a  independently represent —R 5a , —C(O)R 5b , —C(O)OR 5c , —C(O)N(R 6a )R 7a , —S(O) m R 5j  or —S(O) 2 N(R 6h )R 7h ; 
         R 5b  to R 5h , R 5j , R 5k , R 5n , R 6a  to R 6i , R 7a , R 7b , R 7d  and R 7f  to R 7i  independently represent, on each occasion when used herein, H or R Sa ; or 
         any of the pairs R 6a  and R 7a , R 6b  and R 7b , R 6d  and R 7d , R 6f  and R 7f , R 6g  and R 7g , R 6h  and R 7h  or R 6i  and R 7i  may be linked together to form, along with the atom(s) to which they are attached, a 3- to 6-membered ring, which ring optionally contains a further heteroatom (such as nitrogen or oxygen) in addition to the nitrogen atom to which these substituents are necessarily attached, and which ring is optionally substituted by one or more substituents selected from F, Cl, ═O, —OR 5h  and/or R 5a ; 
         R 5i , R 5m  and R 5p  independently represent R 5a ; 
         R 5a  represents, on each occasion when used herein, C 1-6  alkyl optionally substituted by one or more substituents selected from halo, —CN, —N 3 , ═O, —OR 8a , —N(R 8b )R 8c , —S(O) n R 8d , —S(O) 2 N(R 8e )R 8f  and/or —OS(O) 2 N(R 8g )R 8h ; 
         n represents 0, 1 or 2; 
         R 8a , R 8b , R 8d , R 8e  and R 8g  independently represent H or C 1-6  alkyl optionally substituted by one or more substituents selected from halo, ═O, —OR 11a , —N(R 12a )R 12b  and/or —S(O) 2 -M 1 ; 
         R 8c , R 8f  and R 8h  independently represent H, —S(O) 2 CH 3 , —S(O) 2 CF 3  or C 1-6  alkyl optionally substituted by one or more substituents selected from F, Cl, ═O, —OR 13a , —N(R 14a )R 14b  and/or —S(O) 2 -M 2 ; or 
         R 8b  and R 8c , R 8e  and R 8f  or R 8g  and R 8h  may be linked together to form, along with the atom(s) to which they are attached, a 3- to 6-membered ring, which ring optionally contains a further heteroatom (such as nitrogen or oxygen) in addition to the nitrogen atom to which these substituents are necessarily attached, and which ring is optionally substituted by one or more substituents selected from F, Cl, ═O and/or C 1-3  alkyl optionally substituted by one or more substituents selected from ═O and fluoro; 
         M 1  and M 2  independently represent —N(R 15a )R 15b  or C 1-3  alkyl optionally substituted by one or more fluoro atoms; 
         R 11a  and R 13a  independently represent H or C 1-3  alkyl optionally substituted by one or more fluoro atoms; 
         R 12a , R 12b , R 14a , R 14b , R 15a  and R 15b  independently represent H, —CH 3  or —CH 2 CH 3 , 
         T represents T 1 , T 2 , T 3 , T 4 , T 5 , T 6  or T 7 ; 
         T 1  is an aromatic ring represented by the following substructure: 
       
       
         
           
           
               
               
           
         
         in which: 
         (i) W 1  represents —C═;
 W 2  represents —C(R 1 )═ or —C(Y 3 )═; and 
 one of E d1 , E d2  or E d3  represents —N(R 2 )—, —N(Y 4 )—, —O— or —S—, and the other two independently represent —C(R 1 )═, —C(Y 3 )═ or —N═, 
 wherein there is one Y 3  or Y 4  group present; 
 
         (ii) W 1  represents —C═;
 W 2  represents —N(Y 4 )—; 
 E d1 , E d2  and E d3  independently represent —C(R 1 )═ or —N═; or 
 
         iii) W 1  represents —N—;
 W 2  represents —C(R 1 )═ or —C(Y 3 )═; 
 E d1 , E d2  and E d3  independently represent —C(R 1 )═, —C(Y 3 )═ or —N═, 
 wherein there is one Y 3  group present; 
 
         T 2  is an aromatic ring represented by the following substructure: 
       
       
         
           
           
               
               
           
         
         in which: 
         one of E e1 , E e2  E e3  or E e4  represents —C(R 1 )═ and the others independently represent —C(R 1 )═ or —N═; 
         T 3  is an aromatic bicyclic ring represented by the following substructure: 
       
       
         
           
           
               
               
           
         
       
       any three of E f1  to E f7  represent —C(R 1 )═, and the others independently represent —C(R 1 )═ or —N═;
 T 4  is an aromatic bicyclic ring represented by the following substructure: 
 
       
         
           
           
               
               
           
         
         E g1 , E g2 , E g3  and E g5  independently represent —C(R 1 )═ or —N═; 
         one of E g4  and E g6  represents —N(R 2 )—, —O— or —S— and the other represents —C(R 1 )═ or —N═; 
         E g7  and E g8  both represent a carbon atom, or one of E g7  and E g8  represents a carbon atom and the other represents a nitrogen atom, 
         but wherein in the bicyclic ring, no more than four nitrogen atoms are present (i.e. no more than four of E g1  to E g8  may represent a nitrogen atom represented by —N═ or —N(R 2 )—); 
         T 5  is an aromatic bicyclic ring represented by the following substructure: 
       
       
         
           
           
               
               
           
         
         E h3 , E h4 , E h5  and E h6  independently represent —C(R 1 )═ or —N═; 
         (i) W 3  represents —C═;
 E h1  represents —C(R 1 )═ or —N═; 
 E h2  represents —N(R 2 )—, —O— or —S—, or, provided that E h7  or E h8  is a nitrogen atom, —C(R 1 )═; 
 E h7  and E h8  both represent a carbon atom, or one of E h7  and E h8  represents a carbon atom and the other represents a nitrogen atom; 
 
         (ii) W 3  represents —N—;
 E h1  and E h2  independently represent —C(R 1 )═ or —N═; 
 E h1  and E h8  both represent a carbon atom, 
 
         but wherein in the bicyclic ring, no more than four nitrogen atoms are present (i.e. no more than four of W 3 , and E h1  to E h8  may represent a nitrogen atom represented by —N═ or —N(R 2 )—); 
         T 6  is a ring represented by the following substructure: 
       
       
         
           
           
               
               
           
         
         W 4  represents —C(R 3 )— or —N—; 
         when W 4  represents —C(R 3 )—, then W 5  represents —C(R 3 )(Y 5 )— or —N(Y 6 )—; 
         when W 4  represents —N—, then W 5  represents —C(R 3 )(Y 5 )—; 
         W 6  represents an C 1-5  alkylene or C 1-5  heteroalkylene chain both of which are optionally substituted by one or more substituents selected from G x ; 
         T 7  is a cyclic or acyclic alkene represented by the following substructure: 
       
       
         
           
           
               
               
           
         
         R 4a  and R 4b  independently represent G w , or R 4a  and R 4a  are connected together to form, along with the two alkene carbons to which they are necessarily attached, a C 3-7  cycloalkylene or 3- to 8-membered heterocycloalkylene ring both optionally substituted by one or more substituents selected from G x ; 
         each R 1  represents, on each occasion when used herein, hydrogen, halo, —R 25a , —C(O)R 25b —CN, —C(O)N(R 26a )R 27a , —N(R 26b )R 27b , —N(R 25c )C(O)R 26c , —N(R 25d )C(O)OR 26d , —OR 25e , —OS(O) 2 R 25f , —S(O) m1 R 25g , —OC(O)R 25h  or —S(O) 2 N(R 26e )R 27e ; 
         each R 2  represents, on each occasion when used herein, hydrogen, —R 25a , —C(O)R 25b  or —C(O)N(R 26a )R 27a ; 
         each R 3  represents, on each occasion when used herein, hydrogen, —R 35a , —CN, —N(R 36b )R 37b  or —OR 35d ; 
         G w  represents hydrogen, halo, —R 45a , —C(O)R 45b , —CN, —C(O)N(R 46a )R 47a , —N(R 46b )R 47b , —N(R 45c )C(O)R 46c , —N(R 45d )C(O)OR 46d , —OR 45e , —OS(O) 2 R 45f , —S(O) m1 R 45g , —OC(O)R 45h  or —S(O) 2 N(R 46e )R 47e ; 
         G x  represents F, —R 55a , —C(O)R 55b , —CN, —C(O)N(R 56a )R 57a , —N(R 56b )R 57b , —N(R 55c )C(O)R 56c , —N(R 55d )C(O)OR 56d , —OR 55e , —OS(O) 2 R 55f , —S(O) m1 R 55g , —OC(O)R 55 ″, —S(O) 2 N(R 56e )R 57e  or ═O; 
         m1 represents, on each occasion when used herein, 0, 1 or 2; 
         R 25b  to R 25e , R 25g , R 25h , R 26a  to R 26e , R 27a , R 27b  and R 27e  independently represent, on each occasion when used herein, H or R 25a ; or 
         any of the pairs R 26a  and R 27a , R 26b  and R 27b , R 26e  and R 27e , may be linked together to form, along with the atom(s) to which they are attached, a 3- to 6-membered ring, which ring optionally contains a further heteroatom (such as nitrogen or oxygen) in addition to the nitrogen atom to which these substituents are necessarily attached, and which ring is optionally substituted by one or more substituents selected from fluoro, ═O, —O—C 1-4  alkyl and/or C 1-4  alkyl; 
         R 25f  represents R 25a ; 
         R 36b , R 37b  and R 35d  independently represent hydrogen or R 35a ; or 
         R 36b  and R 37b  may be linked together to form a 3- to 6-membered ring optionally containing one further heteroatom, and which ring is optionally substituted by one or more substituents selected from F and methyl; 
         R 45b , R 46a , R 47a , R 46c , R 46d , R 45h , R 46e  and R 47e  independently represent hydrogen or R 45a ; 
         R 45g , R 46b , R 47b , R 45c , R 45d , R 45e  and R 45f  independently represent R 45a ; or 
         any of the pairs R 46a  and R 47a , R 46b  and R 47b , and R 46e  and R 47e  may be linked together to form a 3- to 6-membered ring optionally containing one further heteroatom, and which ring is optionally substituted by one or more substituents selected from F and methyl; 
         R 55b  to R 55e , R 55g , R 55h , R 56a  to R 56e , R 57a , R 57b  and R 57e  independently represent, on each occasion when used herein, H or R 55a ; or 
         any of the pairs R 56e  and R 57a , R 56b  and R 57b , R 56e  and R 57e , may be linked together to form a 3- to 6-membered ring optionally containing one further heteroatom, and which ring is optionally substituted by one or more substituents selected from F and methyl; 
         R 25a  represents, on each occasion when used herein, C 1-6  alkyl optionally substituted by one or more substituents selected from fluoro, —CN, ═O and —O—C 1-4  alkyl; 
         R 35a , R 45a  and R 55a  independently represent C 1-4  alkyl optionally substituted by one or more fluoro atoms; 
         Y 2 , Y 3 , Y 4 , Y 5 , Y 6  and Y 7  independently represent, on each occasion when used herein: 
         (a) an aryl group or a heteroaryl group (both of which groups are optionally substituted by one or more substituents selected from A); or 
         (b) C 1-12  alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G 1  and/or Z 1 , 
         but wherein at least one Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7  group is present that represents an aryl group or a heteroaryl group (both of which groups are optionally substituted by one or more substituents selected from A); 
         A represents, on each occasion when used herein: 
         I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from B; 
         II) C 1-8  alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G 1  and/or Z 1 ; or 
         III) a G 1  group; 
         G 1  represents, on each occasion when used herein, halo, cyano, —N 3 , —NO 2 , —ONO 2  or -A 1 -R 16a ; 
         wherein A 1  represents a single bond or a spacer group selected from —C(O)A 2 -, —S—, —S(O) mx A 3 -, —N(R 17a )A 4 - or —OA 5 -, in which: 
         A 2  represents a single bond, —O—, —N(R 17b )— or —C(O)—; 
         A 3  represents a single bond, —O— or —N(R 17c )—; 
         A 4  and A 5  independently represent a single bond, —C(O)—, —C(O)N(R 17d )—, —C(O)O—, —S(O) 2 — or —S(O) 2 N(R 17e )—; 
         Z 1  represents, on each occasion when used herein, ═O, ═S, ═NOR 16b , ═NS(O) 2 N(R 17f )R 16c , ═NCN or ═C(H)NO 2 ; 
         B represents, on each occasion when used herein: 
         I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G 2 ; 
         II) C 1-8  alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G 2  and/or Z 2 ; or 
         III) a G 2  group; 
         G 2  represents, on each occasion when used herein, halo, cyano, —N 3 , —NO 2 , —ONO 2  or -A 6 -R 18a ; 
         wherein A 6  represents a single bond or a spacer group selected from —C(O)A 7 -, —S—, —N(R 19a )A 9 - or —OA 10 -, in which: 
         A 7  represents a single bond, —O—, —N(R 19b )— or —C(O)—; 
         A 8  represents a single bond, —O— or —N(R 19c )—; 
         A 9  and A 10  independently represent a single bond, —C(O)—, —C(O)N(R 19d )—, —C(O)O—, —S(O) 2 — or —S(O) 2 N(R 19e )—; 
         Z 2  represents, on each occasion when used herein, ═O, ═S, ═NOR 18b , ═NS(O) 2 N(R 19f )R 18c , ═NCN or ═C(H)NO 2 ; 
         R 16a , R 16b , R 16c , R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 18a , R 18b , R 18c , R 19a , R 19b , R 19c , R 19d , R 19e  and R 19f  are independently selected from: 
         i) hydrogen; 
         ii) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G 3 ; 
         iii) C 1-8  alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G 3  and/or Z 3 ; or 
         any pair of R 16a  to R 16c  and R 17a  to R 17f , and/or R 18a  to R 18c  and R 19a  to R 19f , may, for example when present on the same or on adjacent atoms, be linked together to form with those, or other relevant, atoms a further 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 double bonds, which ring is optionally substituted by one or more substituents selected from G 3  and/or Z 3 ; 
         G 3  represents, on each occasion when used herein, halo, cyano, —N 3 , —NO 2 , —ONO 2  or -A 11 -R 20a ; 
         wherein A 11  represents a single bond or a spacer group selected from —C(O)A 12 -, —S—, —S(O) mx A 13 -, —N(R 21a )A 14 - or —OA 16 -, in which: 
         A 12  represents a single bond, —O—, —N(R 2lb )— or —C(O)—; 
         A 13  represents a single bond, —O— or —N(R 21c )—; 
         A 14  and A 15  independently represent a single bond, —C(O)—, —C(O)N(R 21d )—, —C(O)O—, —S(O) 2 — or —S(O) 2 N(R 21e )—; 
         Z 3  represents, on each occasion when used herein, ═O, ═S, ═NOR 20b , ═NS(O) 2 N(R 21f )R 20c , ═NCN or ═C(H)NO 2 ; 
         R 20a , R 20b , R 20c , R 21a , R 21b , R 21c , R 21d , R 21e  and R 21f  are independently selected from: 
         i) hydrogen; 
         ii) C 1-6  alkyl or a heterocycloalkyl group, both of which groups are optionally substituted by one or more substituents selected from halo, C 1-4  alkyl, —N(R 22a )R 23a , —OR 22b  and ═O; and 
         iii) an aryl or heteroaryl group, both of which are optionally substituted by one or more substituents selected from halo, C 1-4  alkyl (optionally substituted by one or more substituents selected from ═O, fluoro and chloro), —N(R 22c )R 23b  and —OR 22d ; or 
         any pair of R 20a  to R 20c  and R 21a  to R 21f  may, for example when present on the same or on adjacent atoms, be linked together to form with those, or other relevant, atoms a further 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 or 2 double bonds, which ring) is optionally substituted by one or more substituents selected from halo, C 1-4  alkyl, —N(R 22e )R 23c , —OR 22f  and ═O; 
         Y 1  and Y 1a  independently represent —C(O)OR 9a  or 5-tetrazolyl; 
         R 9a  represents hydrogen or C 1-4  alkyl optionally substituted by one or more halo atoms; 
         and L 1a  independently represent a single bond or —(CH 2 ) p -Q-(CH 2 ) q —; 
         Q represents —C(R y1 )(R y2 )—, —C(O)—, —N(R y3 )— or —O—; 
         p and q independently represent 0, 1 or 2, but wherein the sum of p and q does not exceed 2; 
         L 2  represents a single bond or a spacer group selected from —C(R y4 )(R y5 )—, —N(R 17a )-A 16 -, and —OA 17 -; 
         A 16  represents a direct bond, —C(O)—, —C(O)N(R 17b )—, —C(O)C(R y6 )(R y7 )— or —S(O) 2 —; 
         A 17  represents a direct bond or —C(R y8 )(R y9 )—; 
         R y1 , R y2 , R y4 , R y5 , R y6 , R y7 , R y8  and R y9  independently represent H, fluoro or C 1-3  alkyl optionally substituted by one or more fluoro atoms; or 
         R y1  and R y2 , R y4  and R y5 , R y6  and R y7  and R y8  and R y9  may be linked together to form a 3- to 6-membered ring optionally substituted by one or more substituents selected from fluoro and C 1-2  alkyl; 
         R y3  represents hydrogen or C 1-3  alkyl; 
         R 17a  and R 17b  independently represent hydrogen, C 1-6  alkyl (optionally substituted by one or more substituents selected from fluoro, —CN, —OH, —OCH 3 , —OCH 2 CH 3  and/or ═O), aryl or heteroaryl (both of which latter two groups are optionally substituted by one or more substituents selected from halo, —R 18a , —C(O)R 18b , —CN, —C(O)N(R 18c )R 18d , —N(R 18e )R 18f , —N(R 18g )C(O)R 18h , —N(R 18i )C(O)OR 18j , —OR 18k , —OS(O) 2 R 18m , —S(O) m R 18n , —OC(O)R 18p  or —S(O) 2 N(R 18q )R 18r ); 
         m represents, on each occasion when used herein, 0, 1 or 2; 
         mx represents, on each occasion when used herein, 1 or 2; 
         R 18a , R 18b , R 18c , R 18d , R 18e , R 18f , R 18g , R 18h , R 18i , R 18j , R 18k , R 18n , R 18p , R 18q  and R 18r  independently represent hydrogen or C 1-3  alkyl optionally substituted by one or more fluoro atoms; 
         R 18m  represents C 1-3  alkyl optionally substituted by one or more fluoro atoms; 
         or a pharmaceutically-acceptable salt thereof. 
       
     
     
         2 . A compound as claimed in  claim 1 , wherein the compounds of formula I represents: 
       
         
           
           
               
               
           
         
         in which: 
         Y represents —C(O)— or —C(═N—OR 28 )—; 
         R 28  represents hydrogen or C 1-4  (e.g. C 1-2 ) alkyl; 
         D 1 , D 2  and D 3  respectively represent —C(R 1a )═, —C(R 1b )═ and —C(R 1c )═; 
         R 1a , R 1b  and R 1c  independently represent hydrogen, R 5a , halo or —CN; 
         each of E a1 , E a2 , E a4  and E a5  respectively represent —C(H)═, —C(R 2b )═, —C(R 2d )═ and —C(H)═, or, one or two of E a1 , E a2 , E a4  and E a5  may alternatively and independently represent —N═; 
         R 2b  and R 2d  independently represent hydrogen or a substituent selected from X 1 ; 
         X 1  represents a group selected from R 5a , halo or —CN; 
         R 5a  represents, on each occasion when used herein, C 1-6  alkyl optionally substituted by one or more substituents selected from ═O, halo, —CN and —N 3 ; 
         Y 1  represents —C(O)OR 9a ; 
         T represents T 1 , T 2 , T 5  or T 7 , i.e.: 
       
       
         
           
           
               
               
           
         
         W 1  represents —N— or —C═; 
         E d1  represents —N═ or —C(R 1 )═; 
         E d2  represents —N═, —C(R 1 )═ or —C(Y 3 )═; 
         E d3  represents —N═, —C(Y 3 )═ or —C(R 1 )═; 
         W 2  represents —C(Y 3 )═ or —C(R 1 )═ or, when W 1  represents —C—, then W 2  may represent —N(Y 4 )═; 
         E e1 , E e2 , E e3  and E e4  independently represent —C(R 1 )═(in which each R 1  is preferably hydrogen); 
         W 3  represents —N—; 
         E h2  represents —N—; 
         E h1  represents —C(R 1 )═; 
         E h3 , E h4 , H h5  and E h6  independently represent —C(R 1 )═; 
         R 4a  and R 4b  independently represent hydrogen; 
         Y 2 , Y 3 , Y 4  and Y 7  independently represent aryl or pyridyl, both of which are optionally substituted by one or more substituents selected from A; 
         each R 1  independently represents hydrogen, halo, —CN or R 25a ; 
         R 25a  represents C 1-6  alkyl optionally substituted by one or more fluoro substituents; 
         A represents G 1  or C 1-6  alkyl optionally substituted by one or more substituents selected from G 1 ; 
         G 1  represents halo; 
         R 9a  represents hydrogen or C 1-6  alkyl; 
         L 1  independently represent a single bond; 
         L 2  represents —N(R 17a )-A 16 - or —OA 17 -; 
         A 16  and A 17  independently represent a direct bond; 
         R 17a  represents hydrogen or C 1-6  alkyl. 
       
     
     
         3 . A compound as claimed in  claim 1 , wherein:
 T 1  represents (when W 1  represents —N—):   
       
         
           
           
               
               
           
         
         T 1  represents (when W 1  represents —C═): 
       
       
         
           
           
               
               
           
         
         T 2  represents: 
       
       
         
           
           
               
               
           
         
         T 5  represents: 
       
       
         
           
           
               
               
           
         
       
       in which each R 1  is independent and as defined in  claim 1  or  claim 2 , and Y 3  is as defined in  claim 1  or  claim 2 . 
     
     
         4 . A compound as claimed in  claim 1 , wherein:
 R 1a , R 1b  and R 1c  independently represent hydrogen;   ring A represents ring (I) (as depicted in  claim 2 );   E a1  and E a5  independently represent —C(H)═ or either one of these represents —N═;   E a2 , E a3  and E a4  respectively represent —C(R 2b )═, —C(R 2c )═ and —C(R 2d )═;   R 2b  represents H;   R 2c  represents the requisite -L 2 -Y 2  group (as depicted in  claim 2 );   R 2d  represents H;   T represents T 1  or T 5 ;   W 1  represents —N—;   E d1  represents —C(R 1 )═ or, preferably, —N═;   E d2  represents —N═;   E d3  represents —C(R 1 )═ or —C(Y 3 )═;   W 2  represents —C(R 1 )═ or —C(Y 3 )═;   one of E d3  and W 2  represents —C(R 1 )═ and the other represents —C(Y 3 )═;   Y 2  and Y 3 , Y 4 , Y 5 , Y 6  or Y 7  both represent aryl or heteroaryl optionally substituted as defined in   any one of the preceding claims;   W 3  represents —N—;   E h2  represents —N═;   E h1 , E h3 , E h4 , E h5 , E h6 , E h7  and independently represent —C(R 1 )═;   R 1  represents hydrogen or R 25a ;   R 25a  represents C 1-3  alkyl;   there are no -L 1a -Y 1a  groups present;   R 17a  represents hydrogen or C 1-6  alkyl optionally substituted by one or more substituents selected from —OCH 3  and —CN;   G 1  represents halo or -A 1 -R 16a ;   A 1  represents a single bond or —OA 5 -;   A 5  represents a single bond;   R 16a  represents hydrogen or C 1-6  alkyl optionally substituted by one or more substituents selected from G 3 ; and/or   G 3  represents halo.   
     
     
         5 . A compound as claimed in  claim 1 , wherein when there is a Y 3 , Y 4 , Y 5 , Y 6  or Y 7  group present, then it represents: a cycloalkyl or heterocycloalkyl group (both of which are optionally substituted by one or more substituents selected from G 1  and/or Z 1 ) or aryl or heteroaryl (both of which are optionally substituted by one or more substituents selected from A). 
     
     
         6 . A compound as claimed in  claim 1 , wherein both Y 2  and, if present, Y 3  to Y 7  represent aryl or heteroaryl (both of which are optionally substituted by one or more substituents selected from A). 
     
     
         7 . A compound of formula I as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical. 
     
     
         8 . A pharmaceutical formulation including a compound of formula I, as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. 
     
     
         9 . A compound, as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease in which inhibition of the synthesis of leukotriene C 4  is desired and/or required. 
     
     
         10 . (canceled) 
     
     
         11 . A compound as claimed in  claim 9 , wherein the disease is a respiratory disease, inflammation and/or has an inflammatory component. 
     
     
         12 . A compound as claimed in  claim 11  wherein the disease is an allergic disorder, asthma, childhood wheezing, a chronic obstructive pulmonary disease, bronchopulmonary dysplasia, cystic fibrosis, an interstitial lung disease, an ear nose and throat disease, an eye disease, a skin diseases, a rheumatic disease, vasculitis, a cardiovascular disease, a gastrointestinal disease, a urologic disease, a disease of the central nervous system, an endocrine disease, urticaria, anaphylaxis, angioedema, oedema in Kwashiorkor, dysmenorrhea, a burn-induced oxidative injury, multiple trauma, pain, toxic oil syndrome, endotoxin chock, sepsis, a bacterial infection, a fungal infection, a viral infection, sickle cell anaemia, hypereosinofilic syndrome, or a malignancy. 
     
     
         13 . A compound as claimed in  claim 12 , wherein the disease is an allergic disorder, asthma, rhinitis, conjunctivitis, COPD, cystic fibrosis, dermatitis, urticaria, an eosinophilic gastrointestinal disease, an inflammatory bowel disease, rheumatoid arthritis, osteoarthritis or pain. 
     
     
         14 . A method of treatment of a disease in which inhibition of the synthesis of leukotriene C 4  is desired and/or required, which method comprises administration of a therapeutically effective amount of a compound of formula I as defined in  claim 1 , or a pharmaceutically-acceptable salt thereof, to a patient suffering from, or susceptible to, such a condition. 
     
     
         15 . A combination product comprising:
 (A) a compound of formula I as defined in  claim 1 , or a pharmaceutically-acceptable salt thereof; and   (B) another therapeutic agent that is useful in the treatment of a respiratory disorder and/or inflammation,   wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.   
     
     
         16 . A combination product as claimed in  claim 15  which comprises a pharmaceutical formulation including a compound of formula I as defined in  claim 1 , or a pharmaceutically-acceptable salt thereof, another therapeutic agent that is useful in the treatment of a respiratory disorder and/or inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier. 
     
     
         17 . A combination product as claimed in  claim 15  which comprises a kit of parts comprising components:
 (a) a pharmaceutical formulation including a compound of formula I as defined in  claim 1 , or a pharmaceutically-acceptable salt thereof, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and 
 (b) a pharmaceutical formulation including another therapeutic agent that is useful in the treatment of a respiratory disorder and/or inflammation in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, 
 which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other. 
 
     
     
         18 . A process for the preparation of a compound of formula I as defined in  claim 1 , which process comprises:
 (i) for compounds of formula I in which Y represents —C(O)—, oxidation of a compound of formula II,   
       
         
           
           
               
               
           
         
         wherein ring A, D 1 , D 2a , D 2b , D 3 , L 1 , Y 1 , L 2  and Y 2  are as defined in  claim 1 ; 
         (ii) for compounds of formula I in which L 2  represents —N(R 17a )A 16 - in which R 17a  represents H, reaction of a compound of formula III, 
       
       
         
           
           
               
               
           
         
         or a protected derivative thereof wherein L 2a  represents —NH 2 , and Y, ring A, D 1 , D 2a , D 2b , D 3 , L 1  and Y 1  are as defined in  claim 1  with: 
         (A) when A 16  represents —C(O)N(R 17b )—, in which R 17b  represents H:
 (a) a compound of formula IV,
   Y a —N═C═O  IV;
 
 or 
 
 (b) with CO (or a reagent that is a suitable source of CO) or a reagent such as phosgene or triphosgene in the presence of a compound of formula V,
   Y 2 —NH 2   V
 
 
 
         wherein, Y 2  is as defined in  claim 1 ; 
         (B) when A 16  represents a single bond, with a compound of formula VI,
   Y 2 -L a   VI
 
 
         wherein L a  represents a suitable leaving group and Y 2  is as defined in  claim 1 ; 
         (C) when A 16  represents —S(O) 2 —, —C(O)— or —C(O)—C(R y6 )(R y7 )—, with a compound of formula VII,
   Y 2 -A 16a -L a   VII
 
 
         wherein A 16a  represents —S(O) 2 —, —C(O)— or —C(O)—C(R y6 )(R y7 )—, and Y 2  and L a  are as defined above or in  claim 1 ; 
         (iii) for compounds of formula I in which one of L 2  represents —N(R 17a )C(O)N(R 17b )—, in which R 17a  and R 17b  both represent H, and, preferably, Y is —C(O)— or R 28  is C 1-6  alkyl optionally substituted by one or more halo atoms, reaction of a compound of formula VIII, 
       
       
         
           
           
               
               
           
         
         wherein J 1  represents —N═C═O, and Y, ring A, D 1 , D 2a , D 2b , D 3 , L 1  and Y 1  are as defined in  claim 1 , with a compound of formula V as defined above; 
         (iv) for compounds of formula I in which, preferably, Y is —C(O)— or R 28  is C 1-6  alkyl optionally substituted by one or more halo atoms, reaction of a compound of formula IX, 
       
       
         
           
           
               
               
           
         
         wherein Z x  represents a suitable leaving group, and Y, ring A, D 1 , D 2a , D 2b , D 3 , L 1  and Y 1  are as defined in  claim 1 , with a compound of formula X,
   Y 2 -L 2 -H  X
 
 
         wherein L 2  and Y 2  is as defined in  claim 1  or above; 
         (iva) for compounds of formula I in which, preferably, Y is —C(O)— or R 28  is C 1-6  alkyl optionally substituted by one or more halo atoms, reaction of a compound of formula IXA, 
       
       
         
           
           
               
               
           
         
         wherein one of D 2b1  and D 2a1  represents —C(—Z y )═, and the other represents D 2 , Z y  represents (independently) a group defined in respect of Z x  above or, alternatively, Z y  may represent —N 3 , and Y, ring A, D 1 , D 2a , D 2b , D 3 , L 1 , Y 1 , C and Y 2  are as defined in  claim 1 , with a compound of formula XA,
   T-H  XA
 
 
         wherein T is as defined in  claim 1  or, in the case of reaction with a compound of formula IXA in which Z y  is —N 3  (and the compound to be formed is one in which T represents a triazolyl group), with an appropriate alkynyl compound; 
         (v) compounds of formula I in which there is a R 17a  or R 17b  group present that does not represent hydrogen (or if there is R 5 , R 6 , R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , R 16 , R 17  or R 18  group present, which is attached to a heteroatom such as nitrogen or oxygen, and which does/do not represent hydrogen), may be prepared by reaction of a corresponding compound of formula I in which such a group is present that does represent hydrogen with a compound of formula XI,
   R wy -L b   XI
 
 
         wherein R wy  represents either R 17a  or R 17b  (as appropriate) as hereinbefore in  claim 1  provided that it does not represent hydrogen (or R wy  represents a R 5  to R 18  group in which those groups do not represent hydrogen), and L b  represents a suitable leaving group; 
         (vi) for compounds of formula I that contain only saturated alkyl groups, reduction of a corresponding compound of formula I that contains an unsaturation; 
         (vii) for compounds of formula I in which Y 1  and/or, if present, Y 1a  represents —C(O)OR 9a , in which R 9a  represent hydrogen, hydrolysis of a corresponding compound of formula I in which R 9a  does not represent H; 
         (viii) for compounds of formula I in which Y 1  and/or, if present, Y 1a  represents —C(O)OR 9a  and R 9a  does not represent H:
 (A) esterification (or the like) of a corresponding compound of formula I in which R 9a  represents H; or 
 (B) trans-esterification (or the like) of a corresponding compound of formula I in which 
 R 9a  does not represent H (and does not represent the same value of the corresponding 
 R 9a  group in the compound of formula Ito be prepared), 
 
         in the presence of the appropriate alcohol of formula XII,
   R 9za OH  XII
 
 
         in which R 9za  represents R a  provided that it does not represent H; 
         (ix) for compounds of formula I in which Y 1  and/or, if present, Y 1a  represents —C(O)OR 9a , in which R 9a  is other than H, and L 1  is as hereinbefore defined, provided that it does not represent —(CH 2 ) p -Q-(CH 2 ) q — in which p represents 0 and Q represents —O—, reaction of a compound of formula XIII, 
       
       
         
           
           
               
               
           
         
         wherein at least one of L 5  and L 5a  represents an appropriate alkali metal group, a —Mg-halide, a zinc-based group or a suitable leaving group such as halo or —B(OH) 2 , or a protected derivative thereof, and the other may represent -L 1 -Y 1  or -L 1a -Y 1a  (as appropriate), and Y, ring A, D 1 , D 2a , D 2b , D 3 , L 2  and Y 2  are as defined in  claim 1 , with a compound of formula XIV,
   L 6 -L xy -Y b   XIV
 
 
         wherein L xy  represents L 1  or L 1a  as hereinbefore defined (provided that it does not represent —(CH 2 ) p -Q-(CH 2 ) q — in which p represents 0 and Q represents —O—) and Y b  represents —C(O)OR 9a , in which R 9a  is other than H, and L 6  represents a suitable leaving group; 
         (x) compounds of formula I in which L 1  preferably represents a single bond, and Y 1  represents 5-tetrazolyl, or, L 1a  and Y 1a , if present, represent those groups defined by L 1  and Y 1 , may be prepared in accordance with the procedures described in international patent application WO 2006/077366; 
         (xi) for compounds of formula I in which L 1  and/or, if present, L 1a  represent a single bond, and Y 1  and/or, if present, Y 1a  represent —C(O)OR 9a  in which R 9a  is H, reaction of a compound of formula XIII as hereinbefore defined but in which L 6a  represents either:
 (I) an alkali metal; or 
 (II) —Mg-halide, 
 
         with carbon dioxide, followed by acidification; 
         (xii) for compounds of formula I in which L 1  and/or, if present, L 1a  represent a single bond, and Y 1  and/or, if present, Y 1a  represent —C(O)OR 9a , reaction of a corresponding compound of formula XIII as hereinbefore defined but in which L 6a  is a suitable leaving group with CO (or a reagent that is a suitable source of CO), in the presence of a compound of formula XV,
   R 9a OH  XV
 
 
         wherein R 9a  is as defined above; 
         (xiii) for compounds of formula I in which Y represents —C(O)—, reaction of either a compound of formula XVI or XVII, 
       
       
         
           
           
               
               
           
         
         respectively with a compound of formula XVIII or XIX, 
       
       
         
           
           
               
               
           
         
         wherein (in all cases) ring A, D 1 , D 2a , D 2b , D 3 , L 1 , Y 1 , L 2  and Y 2  are as defined in  claim 1 ; 
         (xiv) for compounds of formula I in which Y represents —C(O)—, reaction of either a compound of formula XX or XXI, 
       
       
         
           
           
               
               
           
         
         with a compound of formula XXII or XXIII, 
       
       
         
           
           
               
               
           
         
         respectively, wherein L 5b  represents L 5  as hereinbefore defined provided that it does not represent -L 1 -Y 1 , an alkali metal or a —Mg-halide, and (in all cases) ring A, D 1 , D 2a , D 2b , D 3 , L 1 , Y 1 , L 2  and Y 2  are as defined in  claim 1 ; 
         (xv) for compounds of formula I in which Y represents —C(O)—, reaction of an activated derivative of a compound of formula XVI or XVII as defined above, with a compound of formula XXII or XXIII (as defined above), respectively; 
         (xvi) for compounds of formula I in which Y represents —C(═N—OR 28 )—, reaction of a corresponding compound of formula I, with a compound of formula XXIIIA,
   H 2 N—O—R 28   XXIIIA
 
 
         wherein R 28  is represents hydrogen or C 1-6  alkyl optionally substituted by one or more halo atoms; 
         (xvii) for compounds of formula I in which Y represents —C(═N—OR 28 )— and R 28  represents C 1-6  alkyl optionally substituted by one or more halo atoms, reaction of a corresponding compound of formula I, in which R 28  represents hydrogen, with a compound of formula XXIIIB,
   R 28a -L 7   XXIIIB
 
 
         wherein R 28a  represents R 28 , provided that it does not represent hydrogen and L 7  represents a suitable leaving group. 
       
     
     
         19 . A process for the preparation of a pharmaceutical formulation as defined in  claim 8 , which process comprises bringing into association a compound of formula I, as defined in  claim 1 , or a pharmaceutically acceptable salt thereof with a pharmaceutically-acceptable adjuvant, diluent or carrier. 
     
     
         20 . A process for the preparation of a combination product as defined in  claim 15 , which process comprises bringing into association a compound of formula I, as defined in  claim 1 , or a pharmaceutically acceptable salt thereof with the other therapeutic agent that is useful in the treatment of a respiratory disorder and/or inflammation, and at least one pharmaceutically-acceptable adjuvant, diluent or carrier.